Some 1,4-dihydropyridines having an aliphatic group at position 4 of the ring, show a strong PAF-antagonistic activity not described until now (German Patent DE 3,801,717, 24th May 1989).
Surprisingly, the modulation of the side-chain at position 3 of the said ring has led to new molecules with antagonistic activity of the PAF receiver, having greater specificity, power and a much longer duration of the effect than those described in the aforementioned patent.
The chemical structure of the PAF-"acether was identified as 1-O-hexadecyl/octodecyl-2-acetyl-sn-glycero-3-phosphocoline. This compound is a phospholipidic autacoid and a mediator of extremely potent inflammatory reactions liberated by several types of cell, human tissues and experiment animals. These cells are mainly basophile, eosinophile and neutrophile granulocytes, tissue macrophages and monocutes of the peripheral blood, platelets, glandular epithelium cells, endothelial cells and neuronic tissue. The PAF-"acether" is powerful inducer of the systemic aggregation and hypotension. This effect is due to its capacity of promoting the peripheral vasodilatation, but also influences its action over pulmonary circulation and the heart, since it produces diminution of the miocardic contractility and coronary flow. Another effect of the PAF-"acether" is that of inducing bronchoconstriction at doses 100 times lower than histamine. It has also been described that the PAF-"acether" and thus, PAF-"acether" antagonists directly and indirectly regulate the lymphocyte function.
Due to all these effects, the PAF has been described as the main mediator of immunological and inflammatory illnesses.
On this basis, specific inhibitors of biosynthesis and/or the effects of the PAF-"acether" could represent a new class of therapeutic agents, especially in pulmonary illnesses like bronchial asthma, allergic pneumonitis and adult respiratory distress, in which some PAF-"acether" antagonists have reduced or abolished anaphylactic reactions and hypersensitiveness, endotoxic shock and gastric ulcers. Also, the participation of the PAF-"acether" has been demonstrated in a series of pathologic states of an immunoallergic nature like inflammatory processes, psoriasis, glomerulonephritis and transplant rejection.
Some Ca++ antagonists also present PAF antagonistic properties, as is the case with Diltiazem and Gallopamil. However, not all the Ca++ channel blocking agents have this activity. So, the 1,4-dihydropyridines, like Nifedipina, only show a very weak activity, since the concentrations needed to obtain an effect are 1,000,000 higher than those inhibiting calcium flow in other cells and, at least, 1,000 times greater than the specific antagonists of the PAF-"acether".
The invention, therefore, is referred to a series of new 1,4-dihydropyridines corresponding to formula (i) with antagonistic activity of the PAF-"acether", to the pharmaceutical compositions that contain them and their methods of preparation: ##STR2## where: R is a saturated alkyl chain of C1-C2 like methyl or ethyl
R' is a saturated or unsaturated alkyl chain of C1-C16, lineal, branched or cyclic, such as methyl, ethyl, isopropyl, tertiary-butyl, n-hexyl, n-hexadecyl, allyl, 1-undecenyl and cinnamyl. It can also be interrupted by an oxygen atom, like 2-methoxyethyl or tetrahydrofurfuryl and can also represent the 2-(N-morpholine) ethyl grouping PA1 n is a number that can be 2 and 3 PA1 X defines an oxygen atom (O), or sulphur (S), or a SO2 grouping PA1 Ar represents an aromatic ring such as phenyl except in those compounds having X=S and n=2. It also represents a substituted phenyl group such as 4-nitrophenyl, 4-acetylaminophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methylphenyl, 4-methoxyphenyl, 3-dimethyl-aminophenyl, 4-biphenyl, 4-phenoxyphenyl, 4-benzylphenyl, 4-benzyloxyphenyl. It can also represent the 1-naphthyl and 2-naphthyl groups.
The pharmacological activity of compounds of formula (I) have been established as is indicated later on.
The compounds can be obtained using known methods already described in the literature: